Obesity is known to be associated with serious risk factors, and there is currently intense interest in identifying new principles for treatment of this condition. These efforts have hitherto resulted in identification of a substantial number of potential central and peripheral targets for treatment. It has also been shown that growth hormone (GH), more specifically human growth hormone (hGH) in human beings, acts as a potent regulator of body fat storage, and thus promotes breakdown of adipose tissue in obese humans while preserving lean tissues. Since a large proportion of glucose disposal and energy expenditure is thought to take place in lean tissues, preservation of such tissues combined with a selective loss of adiposity appears to be a highly desirable objective.
Although it is known that the protein anabolic aspect of the GH—insulin like growth factor-1 axis is influenced by diet composition, there does not appear to have been any focus on the question of whether this is also true for GH-stimulated loss of adipose tissue. The effect of GH during restriction of energy intake has also been unclear. There have been some reports indicating no additional effects of GH administration compared to the effect of energy restriction alone, whilst other reports have indicated the such effects.
A recently reported study by the present inventors and co-workers indicated GH-stimulated breakdown of adipose tissue in genetically intact old rats that had become obese while receiving a high-fat diet. However, despite normalisation of body fat stores following GH injection, basal insulin levels were significantly elevated.
It has been suggested that an excessive hyperinsulinemic response to GH injections would decrease the net effect of GH on adipose tissue. This would not be surprising since GH and insulin have been suggested to have opposing effects in adipose tissue. Moreover, sustained hyperinsulinemia would also increase the risk of development of overt Type 2 diabetes in susceptible obese individuals that already are at risk.
There is thus a clear need to identify factors determining the insulin response to administration of GH, both from a mechanistic and a safety point of view. The present inventors have now obtained clear indications that the macronutrient composition of the diet received by obese individuals constitutes one such factor, and that total energy intake constitutes another.